The prevalence of obesity continues to rise, along with its metabolic consequences including diabetes, dyslipidemia, hypertension, fatty liver disease, heart disease, and a host of other morbidities. A clear understanding of the genetic architecture of adiposity and its correlated metabolic traits can identify important targets for intervention, either behavioral or pharmaceutical. Significant progress was achieved in the last 4 years of our project in identifying hundreds of common variants associated with adiposity, regional fat distribution, and ectopic fat across 3 major ethnicities; identifying interactions wit physical activity, smoking, gender, and age; identifying pleiotropic loci accounting for the correlated architecture with metabolic traits; and bioinformatic identification of important pathways, tissue specificities, and predicted cellular / organismal functions. In this renewal application, we propose to continue to expand our understanding of the genetic underpinnings of adiposity traits, specifically, body mass index (BMI), measures of centralized obesity (waist- to-hip ratio adjusted for BMI (WHRaBMI) and CT assessed abdominal fat volumes by focusing on rare variation measured by whole exome and whole genome sequencing, carrying out detailed bioinformatic annotation of our findings including predicted functional significance, regulatory function, and pathways using publicly available knowledge databases, and leveraging our collaboration with ENCODE investigators. Finally, we propose to carry out functional mapping and evaluation of our discoveries in humans in a Drosophila model of adiposity and diet-induced diabetes. We will interrogate GWAS-identified genomic regions, by assessing the effect of knock-downs and knock-outs of functional elements (genes, regulatory loci) in those regions on Drosophila adiposity and metabolic phenotypes. This functional mapping will identify genes in the regions of association that influence adiposity traits, providing gene targets for investigation in the human sequence resource. Our basis of operation is within the CHARGE consortium with its outstanding resources and investigators, and with our established collaboration with other consortia, in particular, GIANT. These powerful approaches for discovery, annotation, and screening for functional significance will allow us to expand our knowledge and understanding of the genetic architecture of obesity with the potential to identify pathways / targets amenable to pharmaceutical or behavioral intervention.